Abstract
New steroidal imidazolidine derivatives (7-9) were synthesized by reacting steroidal thiosemicarbazones (4-6) with ethyl-2-chloroacetate in absolute ethanol. After characterization by spectral and analytical data, the interaction studies of compounds (7-9) with DNA were carried out by UV-vis, luminescence spectroscopy, circular dichroism and gel electrophoresis. The compounds bind to DNA preferentially through electrostatic and hydrophobic interactions with Kb; 2.07 × 104 M-1, 2.1 × 104 M–1 and 1.9 × 104 M–1, respectively indicating the higher binding affinity of compound 8 towards DNA. Gel electrophoresis demonstrated that the compound 8 show strong interaction with DNA and during its cleavage activity with pBR322 DNA, it seems to follow the mechanistic pathway, involving singlet oxygen and superoxide anion to generate ROS responsible for initiating DNA strand scission. The docking study suggested the intercalation of imidazolidine moiety of steroid derivative in minor groove of DNA. In MTT assay, compounds 7-9 revealed potential toxicity against different human cancer cells especially compound 8 against A549 cells. Genotoxicity of compounds (7-9) was checked by comet assay. In western blotting, the expressions of relevant apoptotic markers depicted an apoptosis by steroidal imidazolidines in A549 cells.
Highlights
Synthetic chemistry has gained enormous popularity for its important role in drug discovery over the last few decades
In continuation of our previous work [18] we report the synthesis of new steroidal imidazolidines as metal free DNA binding agents
Thin layer chromatography (TLC) plates were coated with silica gel G and exposed to iodine vapours to check the homogeneity as well as the progress of reaction
Summary
Synthetic chemistry has gained enormous popularity for its important role in drug discovery over the last few decades. Because of the drug tolerance problems, there is always scope for the design and development of new and modified analogs as more efficient drug candidates. This has been done through the rational design and synthesis of receptor based lead molecules which still remains an open area. Substituted imidazolidine derivatives, an important class of heterocyclic compounds are central substructures of many compounds exhibiting biological and pharmacological properties [2,3] They exhibit a wide range of biological activities such as nitric-oxide synthase inhibition, anti-inflammatory, anti-parasitic, antimicrobial, analgesic, α-adrenergic receptor agonist, hypoglycemic, anticonvulsant and potential cyclooxygenase-2 (COX-2) inhibition [4,5,6,7,8,9,10,11,12]
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